PDGFRα + pericryptal stromal cells are the critical source of Wnts and RSPO3 for murine intestinal stem cells in vivo.

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  • Additional Information
    • Source:
      Publisher: National Academy of Sciences Country of Publication: United States NLM ID: 7505876 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1091-6490 (Electronic) Linking ISSN: 00278424 NLM ISO Abbreviation: Proc Natl Acad Sci U S A Subsets: MEDLINE
    • Publication Information:
      Original Publication: Washington, DC : National Academy of Sciences
    • Subject Terms:
      Epithelial Cells/*cytology ; Intestines/*cytology ; Receptor, Platelet-Derived Growth Factor alpha/*physiology ; Stem Cell Niche/*physiology ; Stem Cells/*cytology ; Stromal Cells/*cytology ; Thrombospondins/*metabolism ; Wnt1 Protein/*metabolism; Acyltransferases/physiology ; Animals ; Cell Differentiation ; Cell Proliferation ; Epithelial Cells/metabolism ; Homeostasis ; Intestinal Mucosa/metabolism ; Membrane Proteins/physiology ; Mice ; Mice, Inbred C57BL ; Mice, Knockout ; Organoids/cytology ; Organoids/metabolism ; Stem Cells/metabolism ; Stromal Cells/metabolism ; Thrombospondins/genetics ; Wnt1 Protein/genetics
    • Abstract:
      Wnts and R-spondins (RSPOs) support intestinal homeostasis by regulating crypt cell proliferation and differentiation. Ex vivo, Wnts secreted by Paneth cells in organoids can regulate the proliferation and differentiation of Lgr5 -expressing intestinal stem cells. However, in vivo, Paneth cell and indeed all epithelial Wnt production is completely dispensable, and the cellular source of Wnts and RSPOs that maintain the intestinal stem-cell niche is not known. Here we investigated both the source and the functional role of stromal Wnts and RSPO3 in regulation of intestinal homeostasis. RSPO3 is highly expressed in pericryptal myofibroblasts in the lamina propria and is several orders of magnitude more potent than RSPO1 in stimulating both Wnt/β-catenin signaling and organoid growth. Stromal Rspo3 ablation ex vivo resulted in markedly decreased organoid growth that was rescued by exogenous RSPO3 protein. Pdgf receptor alpha ( PdgfRα ) is known to be expressed in pericryptal myofibroblasts. We therefore evaluated if PdgfRα identified the key stromal niche cells. In vivo, Porcn excision in PdgfRα + cells blocked intestinal crypt formation, demonstrating that Wnt production in the stroma is both necessary and sufficient to support the intestinal stem-cell niche. Mice with Rspo3 excision in the PdgfRα + cells had decreased intestinal crypt Wnt/β-catenin signaling and Paneth cell differentiation and were hypersensitive when stressed with dextran sodium sulfate. The data support a model of the intestinal stem-cell niche regulated by both Wnts and RSPO3 supplied predominantly by stromal pericryptal myofibroblasts marked by PdgfRα .
      Competing Interests: The authors declare no conflict of interest.
      (Copyright © 2018 the Author(s). Published by PNAS.)
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    • Contributed Indexing:
      Keywords: R-spondins; Wnt signaling; intestine; myofibroblasts; stroma
    • Accession Number:
      0 (Membrane Proteins)
      0 (R-spondin3 protein, mouse)
      0 (Thrombospondins)
      0 (Wnt1 Protein)
      0 (Wnt1 protein, mouse)
      EC 2.3.- (Acyltransferases)
      EC 2.3.1.- (Porcn protein, mouse)
      EC 2.7.10.1 (Receptor, Platelet-Derived Growth Factor alpha)
    • Publication Date:
      Date Created: 20180322 Date Completed: 20180815 Latest Revision: 20181202
    • Publication Date:
      20231215
    • Accession Number:
      PMC5889626
    • Accession Number:
      10.1073/pnas.1713510115
    • Accession Number:
      29559533